SUMMARY

• RUBATO-Double blind (DB; NCT03153137) was a prospective, multicenter, DB, randomized, placebo-controlled, parallel-group, phase 3, 52-week study to assess the efficacy and safety of OPSUMIT in Fontan-palliated, adult and adolescent patients (N=137).¹
  • The median (interquartile range [IQR]) duration of RUBATO-DB study treatment was similar in the OPSUMIT (52.3 [52-53.1] weeks) and placebo (52.9 [52.1-54.1] weeks) groups.¹
  • The primary endpoint of change in peak oxygen consumption (VO₂) from baseline to week 16 was not met.¹
  • A total of 48 (70.6%) and 44 (63.8%) patients in the OPSUMIT and placebo groups, respectively, reported treatment-emergent adverse events (TEAEs).¹
• Eligible patients entered the single-arm RUBATO-Open label (OL) study (NCT03775421), which was planned to be up to 104 weeks of treatment for each patient, following the completion of the last patient's treatment period in RUBATO-DB.¹
• There are case reports of patients who have a history of Fontan procedure and on OPSUMIT therapy summarized in this letter.^2-4

CLINICAL DATA

Phase 3 Trials

RUBATO Double-blind

RUBATO-DB (NCT03153137) was a prospective, multicenter, randomized, placebo-controlled, parallel-group, phase 3, 52-week study to assess the efficacy and safety of OPSUMIT in Fontan-palliated patients aged 12 years and older (RUBATO-DB) and an open-label (OL) extension trial (RUBATO-OL). Patients were randomized to receive OPSUMIT or placebo.¹

RUBATO-DB: Patients and Study Design

The screening period of RUBATO-DB was ≤30 days), followed by DB treatment up to 52 weeks and a safety follow-up period of ≥30 days following permanent treatment discontinuation. The end-of study corresponded to the last visit performed.¹

Inclusion Criteria: RUBATO-DB enrolled patients aged 12 years and older, who had undergone either a total cavopulmonary connection (TCPC) (intra-atrial lateral tunnel [LT-TCPC] or extracardiac conduit [EC TCPC]) Fontan procedure >1 year before screening and were New York Heart Association functional class (NYHA FC) II or III. TCPC surgeries could occur following a prior classical atrio-pulmonary connection.¹

Exclusion Criteria: Patients were excluded if they showed signs of Fontan palliation deterioration within the past 3 months or had CPET limitations (including pacemakers), peak VO₂ <15 mL/kg/min at baseline, or systolic blood pressure <90 mm Hg (<85 mm Hg for those under 18 years and <150 cm in height) at rest or during CPET at screening or baseline.¹

The primary endpoint was the change in peak VO₂ from baseline to week 16. The secondary endpoints were change in peak VO₂ from baseline to week 52 and change in mean count per minute of daily physical activity (counts/minute) as measured via accelerometer from baseline to week 16. Safety outcomes were also assessed.¹

RUBATO-DB: Results

A total of 137 patients were randomized to OPSUMIT (n=68) and placebo (n=69) treatments.¹ The patient baseline characteristics are presented in the Table: Baseline Characteristics.

A total of 92.7% patients completed DB treatment, and 7 (10.3%) patients in the OPSUMIT group and 3 (4.3%) in the placebo group prematurely discontinued treatment. The median (interquartile range [IQR]) duration of RUBATO-DB study treatment was similar in the OPSUMIT (52.3 [52-53.1] weeks) and placebo (52.9 [52.1-54.1] weeks) groups.¹

RUBATO-DB: Efficacy

The primary endpoint of change in peak VO₂ from baseline to week 16 was not met. Results for the primary endpoint were consistent across pre-defined patient subgroups. No treatment effect was observed in the secondary efficacy endpoints.¹ See the Table: Summary of Efficacy Endpoints (Full Analysis Set) below.

Other Efficacy Endpoints

There were no treatment differences in other exercise capacity endpoints, N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels at week 16, time to Fontan-palliated clinical worsening, or time to Fontan-related morbidity events.¹

DB Study Endpoint: Pharmacokinetics

At weeks 4 and 16 (end-of-treatment), the geometric mean trough concentrations of OPSUMIT were 148 mcg/L and 144 mcg/L, respectively; and the OPSUMIT metabolite level at both the timepoints were 882 mcg/L and 896 mcg/L, respectively. Female patients had slightly higher trough concentrations of OPSUMIT and its metabolite (ACT-132577) than male patients at both time points.¹

RUBATO-DB: Safety

A total of 48 (70.6%) and 44 (63.8%) patients in the OPSUMIT and placebo groups, respectively, reported treatment-emergent adverse events (TEAEs). Hepatic AE of special interests (AESIs) occurred in 5 (7.4%) and 3 (4.5%) patients in the OPSUMIT and placebo groups, respectively. Three (4.4%) patients in the OPSUMIT group and 1 patient in the placebo group (1.4%) reported marked liver test abnormalities, leading to study drug discontinuation in 2 patients in the OPSUMIT group and interruption of study treatment in 1 patient in the placebo group. During the treatment period, no patients reported increase in alanine transaminase (ALT) or aspartate aminotransferase (AST) levels >5 × upper limit of normal (ULN). Edema and fluid retention AESIs occurred in 5 (7.4%) and 2 (2.9%) patients in the OPSUMIT and placebo groups, respectively. Anemia/hemoglobin decrease AESIs occurred in 1 OPSUMIT-treated patient and hypotension AESI occurred in 1 patient in each treatment group.¹ For more information regarding safety, see the Table: Safety Profile below.

RUBATO Open-label Extension

Eligible patients entered the single-arm RUBATO-OL study (NCT03775421), which was planned until 104 weeks of treatment for each patient, following completion of RUBATO-DB by the last patient. Patients received OL OPSUMIT once daily, without revealing the previous RUBATO-DB treatment.¹

RUBATO-OL: Patients and Study Design

Patients who completed week 52 and did not meet the exclusion criteria of RUBATO-DB were enrolled in the RUBATO-OL study and received the first dose of OL OPSUMIT immediately. The treatment period initiated with the first dose of OL OPSUMIT in RUBATO-OL and lasted until whichever of the following occurred first:⁵

• Study treatment up to 104 weeks (2 years) for each patient after the last participant completed the RUBATO-DB treatment period.⁵
• Discontinuation of the study intervention by the patient, investigator, or sponsor.⁵

In RUBATO-OL, the safety follow-up period started the day following the last intake of study treatment and ended 30-35 days thereafter with the RUBATO-OL end-of-study (EOS) visit.⁵

The primary endpoint for RUBATO-OL was safety and tolerability of OPSUMIT. Changes from baseline in peak VO₂, VO₂ at the ventilatory anaerobic threshold (VAT), and mean count per minute of daily physical activity (counts/minute) as measured via accelerometer at the scheduled time points were the exploratory endpoints.¹

RUBATO-DB and RUBATO-OL: Efficacy in Pool Full Analysis Set

There was a decrease in both peak VO₂ and VO₂ at VAT from DB-baseline to OL-week 52. The median (IQR) change in daily physical activity (counts/minute) as measured via accelerometer from DB-baseline to OL-week 52 in the placebo/OPSUMIT group (n=13) was -38.4 (-81.1 to 83.6) counts per minute and in the OPSUMIT/OPSUMIT group (n=17) was 67.3 (-33.2 to 142.5) counts per minute. Over both studies, Fontan-palliated clinical worsening events were reported in 3 patients in the placebo/OPSUMIT group and 6 patients in the OPSUMIT/OPSUMIT group.¹

RUBATO-DB and RUBATO-OL: Safety Data From the Total OPSUMIT Treatment-Emergent Period

During either study, 75.4% of patients experienced ≥1 TEAE while receiving OPSUMIT. COVID-19 (16 [13.1%]), headache (13 [10.7%]) and fatigue (9 [7.4%]) were the most frequently reported TEAEs. Two SAEs related to study intervention were reported (increased AST and ALT in 1 OPSUMIT-treated patient during DB and decreased sperm concentration and decreased spermatozoa progressive motility in 1 DB-placebo patient with a medical history of fertility disorders during OL). OPSUMIT was discontinued in both patients. One DB-placebo patient died during the RUBATO-OL study which was not related to the study intervention. Hepatic AESIs (≥1) were reported in 10 (8.2%) OPSUMIT-treated patients across the RUBATO-DB and RUBATO-OL studies. RUBATO-OL was prematurely discontinued because RUBATO-DB did not meet the primary or secondary endpoints.¹

Evidence From Literature

Evidence gathered from the literature is summarized in Table: OPSUMIT in Patients Who Have Undergone a Fontan Procedure.

Literature Search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, DERWENT^® (and/or other resources, including internal/external databases) was conducted on 13 January 2025.